Loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1) results in disruption of the linear ubiquitination assembly complex (LUBAC). Impairment of LUBAC results in impaired NF-kB activation in response to TNF and IL-1b in fibroblastic cells, but also display enhanced pro-inflammatory responses to TNF and IL-1b in leukocytes. Autosomal recessive complete human HOIL-1/RBCK1 deficiency is a new disorder with unbalanced cellular responses to pro-inflammatory cytokines, resulting in the paradoxical association of auto-inflammation and pyogenic bacterial disease, as well as the surprising development of muscular amylopectinosis. The genome-wide gene expression analysis showed that human HOIL-1 deficiency results in impaired NF-B activation in response to TNF- and IL-1 in fibroblastic cells.

Skin fibroblast cell lines were derived from controls (n=3), patients with deficiencies for RBCK1 (HOIL1) (n=2), MYD88 (n=1), and NEMO (n=1). Cells were cultured for 8 or 24 hours in the presence of TNF (5ng/ml) or IL1B (5ng/ml) or left unstimulated for the same length of time.